The biomedical advances of the 20th century produced a tremendous increase in the human life span and an associated increase in the motivation for understanding how the brain ages. It is not yet clear, however, how the brain changes during normal aging to produce the decline in cognitive ability that generally occurs with senescence. Early indications of widespread loss of neurons or synapses are not supported by contemporary studies, which show only limited and restricted declines in the number of neurons and synapses and the extent of axonal and dendritic arbors. Despite relative constancy in number, however, there is ongoing replacement of neuronal connections throughout the adult nervous system and turnover of neurons in the hippocampus and olfactory bulb. Thus, one must consider whether age-related cognitive deficits may arise from changes in the dynamic replacement of neurons and synapses such that populations of neurons become progressively compromised. This loss of effective replacement also would render the aging brain less capable of responding to challenges such as oxidative stress, contributing to the reported increase in oxidative damage. Demonstrating the regulation of ongoing neuronal birth and death in the adult brain is critical for understanding how the brain ages, as well as for establishing the functional consequences of those changes and the prospects for preventing or reversing them. These experiments will test the ability of a critical growth factor, insulin-like growth factor 1 (IGF-1) to influence neuronal genesis and death in the adult and aging brain normally and after acute oxidative challenge. IGF-1 is critical candidate to regulate ongoing neuronal genesis and survival since it influences cell proliferation, is maintained in the adult brain in regions of neuronal turnover, declines during aging coincident with cognitive changes, and can reverse those changes in old rats. Data from preliminary experiments provide direct evidence for IGF-1-dependent regulation of normal adult neurogenesis and neuronal death. IGF-1 also may modulate the response of the brain to oxidative stress since it influences antioxidant and anti-apoptotic mechanisms. The proposed experiments will test key predictions of the hypothesis that IGF-1 modulates ongoing neuronal genesis and death in the adult brain and plays a critical role in the response of the central nervous system to oxidative stress, such that the age-related decline in IGF-1 results in a progressive decline in the ability of the brain to maintain normal neurogenesis and prevent and repair damage after challenges.